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Atrial Fibrillation

E. Kevin Heist, MD, PhD

Updates in General Internal Medicine for Specialists January 27, 2020

Disclosures

Recipient: Company: Description: Content Area:

Self Abbott Honorarium, Research Grant Medical Device

Self Biotronik Honorarium Medical Device

Self Boston Scientific Honorarium, Research Grant Medical Device

Self Johnson & Johnson Honorarium Medical Device

Self Medtronic Honorarium Medical Device

Self Pfizer Consulting Pharmaceutical

Outline

• Rate vs. Rhythm Control

• Methods of Rhythm Control

– Pharmacologic – Ablation

• Stroke Prevention

– Pharmacologic – Devices

Definitions

• Atrial Fibrillation: rapid, chaotic atrial rhythm, typically with irregular and possibly rapid ventricular response.

• Paroxysmal AF: AF episodes < 7 days in duration • Persistent AF: > 7 days, < 1 year in duration • Long-standing Persistent (Chronic) AF: AF > 1 year in duration • Permanent AF: No plan to try to reverse AF

http://www.atrialfibrillationresearch.nl/atrial-fibrillation/ http://www.atrialfibrillationresearch.nl/atrial-fibrillation/

www.atrialfibrillationresearch.nl

Patient Wearable Monitors to Detect Atrial Fibrillation

Drug Therapy for Rate Control in AF

• Beta Blocker Therapy

• Calcium-Channel Blocker Therapy (Diltiazem, Verapamil)

• Digoxin (increased mortality in some studies)

• Amiodarone (useful in acutely ill patients, chronic use limited by drug toxicity)

RACE II: Intensity of Rate Control

Lenient: resting hr < 110 (rest 93 + 9 bpm achieved) Strict: resting hr < 80 hr mod exercise < 110 (rest 76 + 12 bpm achieved) Primary Outcome: -cardiovascular death -CHF hospitalization -stroke -systemic embolism -bleeding -life threatening arrhythmia

Van Gelder et al, NEJM 2010;362:1363-73

p=ns

Digoxin Use and Overall Mortality

Vamos et al, EHJ 2015;36:1831-8


Vamos et al, EHJ 2015;36:1831-8

AF


Vamos et al, EHJ 2015;36:1831-8

AF

CHF

AV Nodal Ablation/Pacemaker: Definitive Rate Control

• Ablation of the AV node causes complete AV block, makes a patient “pacemaker-dependent”

• Does not prevent atrial fibrillation: the risk of stroke and need for anti-coagulation remains

• Typically reserved for elderly and/or sick patients who can’t be acceptably rate controlled with tolerated medications

Electrical Cardioversion is effective, but…

…Atrial fibrillation often recurs

Medical Rate vs. Rhythm Control: AFFIRM

Wyse et al, NEJM 2002;347:1825-33

Observational Mortality Study of Rate vs. Rhythm Control in 26,130 Canadian Patients (66+ years old)

Ionescu-Ittu et al, Arc Int Med 2012;172:997-1004

Drug Therapy: No Magic Pill…

Rhythm Control: Amiodarone vs. Sotalol vs. Placebo

Singh, BN et al, NEJM 2005;352:1861-72

January et al, JACC 2014

Antiarrhythmic Drug Therapy for AF

Drug Therapy for AF Summary

• Hard endpoints with AF rate control are as good as rhythm control (anti-arrhythmic drugs)

• Beta blockers and calcium channel blockers are good rate control choices, digoxin may increase mortality

• Antiarrhythmic drugs for AF have moderate efficacy and potential for drug toxicity

Ablation Procedures for Atrial Fibrillation

Pulmonary Veins as Triggers of Paroxysmal Atrial Fibrillation

Haissaguerre et al, NEJM 1998;339:659

Pulmonary Vein Isolation: Ablation for Paroxysmal AF

Catheter Ablation vs. Antiarrhythmic Drug Therapy for Paroxysmal AF

*Protocol-Defined Treatment Failure: documented symptomatic atrial fibrillation

Wilber et al, JAMA 2010;303:333-40

AF Ablation Methods: Cryoballoon vs RA Ablation: “Fire and ICE”

Kuck et al, NEJM 2106;374:2234-45

CABANA Study: AF ablation vs drug therapy

Packer et al, JAMA. 2019;321:1261-1274

AF and CHF

Is There Benefit to AF Ablation?

CASTLE-AF AF Ablation vs Medical Therapy in AF with CHF (EF<35%)

Marrouche et al, NEJM 2018;378:417-27

Surgical Approaches to AF

LA RA

Cannom AJC 2000;85:25D

FAST Study: Catheter or Surgical Ablation for AF

Boersma et al, Circ 2012;125:23-30

Catheter Ablation: radiofrequency PVI (additional ablation lines at operator discretion) Surgical Ablation: VATS approach, radiofrequency PVI + LA ganglionated plexus ablation + LAA excision (additional ablation lines at operator discretion)

Conclusion Regarding AF Ablation

• AF catheter ablation is more effective than antiarrhythmic drugs, but is not a guarantee of no AF

• Tools and strategies for AF ablation are evolving

• AF ablation may particularly benefit CHF patients

• Surgical AF ablation (Maze) appears more effective and more risky than catheter AF ablation

Stroke Prevention in Atrial Fibrillation

Stroke Is One of the Most Common and Devastating Complications of AF

• All-cause stroke rate with AF is 5% per year

• AF - independent risk factor for stroke

– ~5-fold increase in stroke risk

– ~15% of all strokes caused by AF

– Stroke risk increases with age

• Stroke risk persists in asymptomatic AF

Fuster V, et al. Circulation. 2006;114:e257-e354. Wolf PA, et al. Stroke. 1991;22:983-988. Page RL, et al. Circulation. 2003;107:1141-1145. Hart RG, et al. J Am Coll Cardiol. 2000;35:183-187.

January et al, JACC 2014;64:e1-76.

Stroke Risk Without Anticoagulation: CHADS2 and CHADS2-VASc

Stroke Risk Without Anticoagulation: CHADS2-VASc

CRYSTAL AF Study Detection of AF in cryptogenic stroke

• 441 patients age > 40 with cryptogenic stroke – No h/o AF and no AF on 24+ hour EKG monitor – Randomized to implantable cardiac monitor or usual care

Sanna et al, NEJM 2014;370:2478-86

Anticoagulation and Antiplatelet Therapy

Warfarin vs Placebo in Stroke Prevention in AF

100% 50% 0% -50% -100%

AFASAK-1

SPAF BAATAF

CAFA

SPINAF

EAFT ALL Trials

Favors Warfarin Favors Placebo/ Control

Hart R, et al. Ann Intern Med. 2007;146:857-867.

Warfarin reduces incidence of stroke by about 64%

Aspirin vs Placebo in Stroke Prevention in AF

Favors Placebo/ Control

Antiplatelet therapy reduces incidence of stroke by about 22%


All Trials

100% 50% 0% -50% -100%

AFASAK-1 SPAF I EAFT ESPS-II LASAF, daily

UK-TIA, 300 mg daily

Favors Antiplatelet

LASAF, alternate day

UK-TIA, 1200 mg daily JAST Aspirin Trials SAFT ESPS II, Dipyridamole ESPS II, Combination

Warfarin vs Antiplatelet Therapy in Stroke Prevention in AF

100% 50% 0% -50% -100% Favors Warfarin Favors Antiplatelet


AFASAK I AFASAK II

Chinese ATAFS EAFT PATAF

SPAF II, ≤ 75 yrs

SPAF II, >75 yrs

Aspirin trials

SIFA ACTIVE-W

NASPEAF

All Trials

Primary outcome: stroke, systemic embolus, MI, vascular death. Connolly et al. Lancet. 2006;367:1903-1912.

ACTIVE* W: Cumulative Risk of Stroke

Years

RR = 1.72 (1.24–2.37), P = 0.001

Clopidogrel + aspirin

Oral anticoagulation therapy

Number at risk Clopidogrel 3335 3168 2419 941 + aspirin Oral anti- 3371 3232 2466 930 coagulation therapy

0 0

0.02

0.04

0.10

0.08

0.06 C

umul

ativ

e H

azar

d R

ates

0.5 1 1.5

Importance of Time within Therapeutic Range Patients Treated at Centers with TTR Below or Above 65%

Connolly S, et al. Circulation. 2008;118:2029-2037.

C+A: clopidogrel plus aspirin; OAC: oral anticoagulation therapy RR: relative risk of stroke C+A vs OAC

Hylek EM, et al. Ann Intern Med. 1994;120:897-902. Hylek EM, et al. N Engl J Med. 1996;335:540-546.

INR

Odds Ratio

0 5 6 8 1 2 3 4 7

5

15

10

1

Ischemic Stroke ICH Therapeutic

Window

Warfarin Has a Narrow Therapeutic Window

Relationship Between Clinical Events and INR Intensity in Patients with Atrial Fibrillation

Atrial Fibrillation Patients – 55%-63% of Their Time in Therapeutic INR Range

Baker W, et al. J Manag Care Pharm. 2009;15:244-252.

An Ideal Anticoagulant

Sobieraj-Teague M, et al. Semin Thromb Hemost. 2009;35:515-524.

Desired Characteristic Practical Advantage

Rapid onset of action No need for overlap with heparin

Wide therapeutic index Increased safety

Minimal side effects Improved compliance; less monitoring

Oral formulation Convenient administration

Predictable anticoagulant response Fixed-dose unmonitored treatment

No food or drug interaction No need for monitoring

Availability of antidote Able to reverse in case of bleeding or urgent surgery

Cost effective Accessibility

Emerging Therapies Factor Xa Inhibitors and Direct Thrombin Inhibitors

Harenberg J. Semin Thromb Hemost. 2009;35:574-586.

Tissue Factor/VIIa

IX

IXa

X

Xa

VIIIa

Va

II IIa

Fibrinogen Fibrin

Idrabiotaparinux

Rivaroxaban* Betrixaban Apixaban* YM150 Edoxaban*

Dabigatran* AZD-0837 *FDA Approved Drugs

Apixaban vs Aspirin– AVERROES

R N = 5,600

Atrial Fibrillation + 1 risk factor Failed or unsuitable for VKA therapy

Screening Phase 0-28 days

Apixaban 5 mg BID (Reduced to 2.5 mg/day for selected patients*)

ASA (81 to 324 mg/day)

*Patients with ≥ 2 of the following: •Age ≥ 80 yrs •Body weight ≤ 60 kg •Serum creatinine ≥ 1.5 mg/dL or 133 μmol/L

Primary efficacy outcome: stroke or systemic embolism Primary safety outcome: major bleeds Other outcomes: myocardial infarction, vascular death, all-cause death

Follow-up @ 1 and 3 months and every 3 months thereafter until study completion

NCT00496769. http://www.clinicaltrials.gov/ct2/show/NCT00496769. Accessed Sept 2010.

Connolly S, et al. http://www.escardio.org/congresses/esc-2010/congress-reports/Pages/708-3-AVERROES.aspx. Accessed Sept 2010.

Apixaban – AVERROES Stroke or Systemic Embolic Event

Months

Cum

ulat

ive

Ris

k 0.05

0.03

0.01

0.0

0 3 6 9 12 18 21

Aspirin

RR = 0.46 95% CI = 0.33–0.64 P < 0.001

Apixaban

No. at Risk ASA 2791 2720 2541 2124 1541 626 329 Apix 2809 2761 2567 2127 1523 617 353

Apixaban – AVERROES


Outcome Apixaban (n = 2809)

Aspirin (n = 2791)

Relative Risk (95% CI) P value

Stroke or systemic embolic event 1.6 3.6 0.46 (0.33-0.64) < 0.001

Stroke, embolic event, MI, or vascular death

4.1 6.2 0.66 (0.53-0.83) < 0.001

Major bleeding 1.4 1.2 1.14 (0.74-1.75) 0.56

Fatal bleeding 0.1 0.1 0.84 (0.26-2.75) 0.77

Intracranial bleeding 0.4 0.3 1.09 (0.50-2.39) 0.83




Aspirin (n = 2791)




4.1 6.2 0.66 (0.53-0.83) < 0.001

Major bleeding 1.4 1.2 1.14 (0.74-1.75) 0.56

Fatal bleeding 0.1 0.1 0.84 (0.26-2.75) 0.77


Efficacy (stroke prevention): Eliquis superior to Aspirin




Aspirin (n = 2791)




4.1 6.2 0.66 (0.53-0.83) < 0.001

Major bleeding 1.4 1.2 1.14 (0.74-1.75) 0.56

Fatal bleeding 0.1 0.1 0.84 (0.26-2.75) 0.77


Safety (bleeding): Eliquis similar to Aspirin

Meta-Analysis: DOACs vs. Warfarin

Stroke or Systemic Embolism

Major Bleeding

Ruff et al, Lancet 2014;383:955-62

Dabig. Rivarox. Apix. Edox.

Dabig. Rivarox. Apix. Edox.

DOACs vs Warfarin and All Cause Mortality

Drug Dose Hazard Ratio (all cause death)

P value (vs. warfarin)

Dabigatran* High Dose (150 mg bid)

0.88 0.051

Low Dose* (110 mg bid)

0.91 0.13

Rivaroxaban 20 or 15 mg daily 0.92 0.15

Apixaban 5 or 2.5 mg bid 0.89 0.047

Edoxaban High Dose (60 or 30 mg daily)

0.92 0.08

Low Dose (30 or 15 mg daily)

0.87 0.006

*Dabigatran 110 mg is not an FDA approved dose for stroke prevention in AF

Approval for DOACs for Atrial Fibrillation

• To reduce risk of stroke for patients with non-valvular* atrial fibrillation – *Valvular atrial fibrillation: mechanical heart valve or moderate/severe mitral

stenosis (biologic valve or any other valve problem = non-valvular AF)

Dabigatran for Mechanical Heart Valves

Dabigatran for Mechanical Heart Valves: RE-ALIGN

Eikelboom et al, NEJM 2013;369:1206-14

Dabigatran for mechanical valve: more clots and more bleeding than warfarin

Outcomes of DOACs vs Warfarin for AF Patients with Mitral Stenosis (off-label use)

-2230 propensity matched patients in Korea with AF and any degree of mitral stenosis (without MV surgery) -Comparison of patients treated with warfarin vs DOAC

Holding/Reversal of anticoagulation

-Holding anticoagulation for planned procedures -Reversal of anticoagulation for emergent bleeding or procedures

Holding anticoagulation for planned procedures

• Does anticoagulation need to be held for the procedure? – Catheter ablation of AF and pacemaker/ICD implants can be safely

performed with uninterrupted warfarin or DOAC

• How long should anticoagulation be held? – Warfarin: 5-7 days – DOACs: 2-3 days (possibly 4 days if renal impairment)

• Is “bridging” anticoagulation required?

Should we “bridge” anti-coagulation before surgery?

• Randomized 1884 patients holding warfarin for 5 days before surgery to dalteparin bridge or control

• Stroke/Embolism/TIA: – Dalteparin: 0.3% – Control: 0.4% (p=NS)

• Major Bleeding

– Dalteparin: 3.2% – Control: 1.3% (p=0.005)

Douketis et al, NEJM: 2015;373:823-33

Reversal of warfarin

• Vitamin K (IV, SQ or PO): slow anticoagulation reversal (0.5-2 days) – Allows the body to synthesize clotting factors

• FFP (Fresh Frozen Plasma) or PCC (Prothrombin Complex Concentrate:

Kcentra): rapid but temporary anticoagulation reversal – Repletes clotting factors

Idarucizumab (Praxbind) for reversal of dabigatran in patients with bleeding/urgent surgery on dabigatran

Pollack et al, NEJM 2015;373:511-20.

Dose: 5gm IV x1 FDA Approved: 10/16/2015

ANNEXA-4: Andexanet Alfa for reversal of Rivaroxaban and Apixaban in patients with bleeding within 18 hours of DOAC

Connolly SJ et al. N Engl J Med 2016;375:1131-1141

Dose: Bolus + 2 hour infusion for patients with bleeding within 18 hours of DOAC FDA Approved: May 4, 2018

Rivaroxaban Reversal Apixaban Reversal

DOAC Reversal Agent in Development

• Ciraparantag* (PER977):

– (small molecule, binds to anticoagulants) – Reversal agent for Direct Thrombin Inhibitors, Factor Xa inhibitors and

LMWH

*Investigational agent, not FDA approved for clinical use

Clinical Challenges With New Anticoagulants

• No validated tests to measure anticoagulation effect • No established therapeutic range • Antidotes in various stages of development • Assessment of compliance more difficult than with

vitamin K antagonists • Potential for unknown long-term adverse events • Balancing cost against efficacy • Lack of head-to-head studies comparing new agents • Paucity of data on special populations (ESRD, prior

major bleeds, extreme elderly, etc)

Cost Effectiveness of DOACs vs Warfarin for AF

• Large meta-analysis of 23 trials, over 94,000 patients

• On balance, DOACs were more effective at stroke prevention vs. warfarin

• DOACs had lower intracranial bleeding than warfarin

• DOACs were generally cost effective vs. warfarin (accounting for all health care costs)

Lopez-Lopez et al, BMJ 2017;359:j5058

Trends in Anticoagulation Use for Atrial Fibrillation

Mechanical Approaches to Stroke Prevention:

LAA Occlusion and Ligation

Left Atrial Appendage (LAA) Closure vs Warfarin for Prevention of Stroke in Patients with AF

Reddy et al, Heart Rhythm Society Late Breaking Trials 2013

Control: warfarin INR 2.0-3.0 Intervention: percutaneous closure of LAA

4 Year Efficacy Composite endpoint of stroke, cardiovascular death, and systemic embolism

• LAA Closure: 2.3%/year • Warfarin: 3.8%/year

4 Year All Cause Mortality • LAA Closure: 3.2%/year • Warfarin: 4.8%/year • Hazard Ratio 0.66, p=0.04

Key Points

• Rate control is non-inferior to rhythm control for asymptomatic patients • Antiarrhythmic drugs have moderate efficacy with risks/side effects

• Ablation is more effective than drug therapy for maintenance of sinus rhythm • Anticoagulation is useful for stroke prevention in AF

• New anticoagulants have an expanding role in stroke prevention

• Left atrial appendage occlusion is an emeriging alternative to anticoagulation

Next Best Steps

• A patient shows up to my clinic with new AF… – Generally not a medical emergency, rarely requires transfer to the ER (*if clinically stable)

– Basic laboratory testing (chemistry panel, thyroid) and structural heart assessment by

echocardiography

– Initial goals are anti-coagulation for stroke prevention and rate control

– Cardioversion as an initial attempt at rhythm control is reasonable, especially for younger and/or symptomatic patients

– Patients with recurrent symptomatic AF after cardioversion can consider anti-arrhythmic drug therapy or AF ablation

My patient has AF and needs surgery…

• Continue rate control and/or antiarrhythmic medicine

• The anticoagulated patient: – Low risk of bleeding: continue anticoagulant – High risk of bleeding: hold anticoagulant

• Warfarin: 5 days • DOAC: 2-3 days • “Bridging” with heparin for AF patients: generally should not be done

Questions?

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